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Aims: Dostarlimab-gxly is a humanized monoclonal antibody of the IgG4 isotype that binds to the programmed cell death protein-1 (PD-1) receptor and blocks its ligands. RUBY (NCT03981796) is a two-part multicentre study in patients with recurrent or primary advanced endometrial cancer. The overall aims were to characterise the population pharmacokinetics (PopPK) from Part 1 of this study, identify relevant covariates of interest, and assess exposure-efficacy/safety (ER) relationships., Methods: A PopPK model developed using GARNET (NCT02715284) study data for dostarlimab monotherapy was externally validated with RUBY Part 1 study data. Subsequently, the model was updated with data across the two studies. Exposure-safety analyses for adverse events related to dostarlimab alone or in combination with standard of care (SOC) were modelled using logistic regression. Exposure-efficacy analysis included Cox proportional hazards analysis of the primary efficacy endpoint of progression-free survival (PFS)., Results: For the model update, 7957 pharmacokinetics observations from 868 patients pooled from both RUBY and GARNET studies were available. The model was consistent with the previous model. Dostarlimab clearance was estimated to be 7.79% lower when dostarlimab was given as SOC combination therapy. However, no significant covariates were clinically relevant. Hepatic or renal impairment did not affect pharmacokinetics. Among the safety endpoints, only rash showed a small yet statistically significant effect (P < .05) in all subjects; however, this was not not deemed clinically relevant. There were no other clinically significant exposure-safety or exposure-PFS relationships., Conclusions: The addition of chemotherapy to dostarlimab had limited effect on dostarlimab PopPK, with no clinically significant covariates or clinically relevant exposure-safety or exposure-PFS relationships., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: The CHAR1ZMA study described real-world duration of first-line maintenance niraparib monotherapy among patients with epithelial ovarian cancer., Methods: This retrospective study used a US nationwide, electronic-health-record-derived, de-identified database. Eligible patients were aged ≥18 years with epithelial ovarian cancer who initiated first-line maintenance niraparib monotherapy (January 2017-December 2022 [inclusive]) following first-line platinum-based chemotherapy. Niraparib monotherapy duration was measured as the time to treatment discontinuation, estimated using Kaplan-Meier methodology, overall and stratified by treatment duration (early discontinuers [≤90 days]; non-early discontinuers [>90 days or did not discontinue]). Analyses were repeated in a sub-group of patients with homologous recombination-deficient tumors., Results: Toxicity was the most common reason for niraparib discontinuation among early discontinuers (67.7%) and was less frequent among non-early discontinuers (18.1%). Dose modifications were less frequent among early discontinuers (29.8%) than non-early discontinuers (53.6%). Disease progression was the most common reason for niraparib discontinuation among non-early discontinuers (74.8%) and was less frequent among early discontinuers (30.4%). The observed median treatment duration was 7.2 months (95% CI 6.0 to 8.1) overall (N = 560) and was 4.5 months longer among non-early discontinuers (11.7 months [95% CI 9.8 to 14.7]; n = 399). In the homologous recombination-deficient sub-group (n = 144), the observed median treatment duration was 11.6 months (95% CI 7.8. to 16.1) and was 5.1 months longer among non-early discontinuers (16.7 months [95% CI 12.0 to 22.8]; n = 114)., Conclusion: In this real-world study of patients with epithelial ovarian cancer receiving first-line maintenance niraparib monotherapy, drug toxicity was the most common reason for treatment discontinuation in early discontinuers. Effective and early clinical management of drug toxicity may help mitigate these adverse events, allowing patients to remain on niraparib maintenance treatment longer and experience the potential full therapeutic benefit., Competing Interests: Declaration of Competing Interests FJB has received financial compensation for serving on advisory boards for GSK, AstraZeneca, Clovis Oncology, ImmunoGen, Merck, Eisai, Myriad Genetics, Daiichi Sankyo, BioNTech, and EMD Serono. Her institution has received financial support for her role as a principal investigator for Natera, Merck, Eisai, Clovis Oncology, ImmunoGen, and BeiGene. TACB, JL, JH, JMS, JAH, JP, and AG are employees of and may hold financial equities in GSK. Furthermore, JP owns stock in Boston Scientific and the UnitedHealth Group. RS has received financial compensation for serving on advisory boards for Merck, Seagen, and Mersana Therapeutics; speakers' bureaus for Merck; and writing for UpToDate. She has also served as a principal investigator for Genentech., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: To assess real-world progression-free survival (rwPFS) and time to next treatment (rwTTNT) among patients with epithelial ovarian cancer (EOC) who received first-line maintenance (1LM) niraparib monotherapy., Patients & Methods: In this US-nationwide, electronic health record-derived, deidentified database study, eligible patients with EOC initiated 1LM niraparib monotherapy (1 January 2017-1 December 2022) following first-line platinum-based chemotherapy. Median rwPFS and rwTTNT were estimated with Kaplan-Meier methodology overall and in a homologous recombination-deficient (HRd) subgroup (further stratified as BRCA wild-type [ BRCA wt] or BRCA -mutated [ BRCA m])., Results: Observed median rwPFS was 11.4 (95% CI, 10.1-12.7) months overall ( N  = 560), 18.2 (95% CI, 13.9-24.2) months for the HRd subgroup ( n  = 144), and 25.4 (95% CI, 15.9-not reached) and 14.2 (95% CI, 8.6-18.6) months for HRd patients with BRCA m and BRCA wt tumors, respectively. Observed median rwTTNT was 12.4 (95% CI, 11.5-13.8) months overall, 19.6 (95% CI, 14.9-23.9) months for the HRd subgroup, and 24.9 (95% CI, 16.0-not reached) and 15.1 (95% CI, 10.3-19.8) months for HRd patients with BRCA m and BRCA wt tumors, respectively., Conclusions: The real-world observed median rwPFS and rwTTNT were longer for patients with EOC who received 1LM niraparib monotherapy in the HRd subgroup (specifically for the BRCA m subgroup).

Objective: Among gynecologic cancer patients, it is unclear whether participation in clinical trials impacts survival outcomes. In addition, given the known racial and ethnic disparities in gynecologic cancer trial enrollment, it is important to assess whether clinical trial enrollment is similarly related to overall survival among racial and ethnic minorities. Therefore, we examined associations between clinical trial enrollment and overall survival and potential effect modification by race/ethnicity and cancer site among gynecologic cancer patients., Methods: We used the National Cancer Database to identify women diagnosed with a cervical, ovarian, or uterine cancer from 2004 to 2020 (N = 861,817). Race/ethnicity categories included American Indian/Alaska Native, Asian, Black, Hispanic (any race), Native Hawaiian/Pacific Islander, and White. We used stratified Cox proportional hazards regression to estimate univariable and multivariable-adjusted hazard ratios and 95% confidence intervals for associations of clinical trial enrollment and overall survival. Effect modification by race/ethnicity and cancer site was assessed with multiplicative interaction terms in separate models., Results: Among 861,817 gynecologic cancer patients included, less than 0.1% were enrolled in a clinical trial (n = 881). Median follow-up was 56.0 months (range 0.03-229.4 months). Clinical trial enrollment was related to improved overall survival among gynecologic cancer patients in the overall study population (hazard ratio = 0.90, 95% confidence interval = 0.82-0.99). Neither race/ethnicity (p = 0.34) nor cancer site (p = 0.09) modified the association., Conclusion: Despite the low clinical trial enrollment prevalence, enrollment was associated with improved outcomes for gynecologic cancer patients. These findings are important in demonstrating that participation in clinical trials, regardless of therapeutic treatment assignment, is related to better outcomes., Competing Interests: Declaration of competing interest Dr. Plascak reports honoraria payments from National Comprehensive Cancer Network, North American Association of Central Cancer Registries, and MJH Life Sciences. Dr. Backes reports personal fees from UptoDate, Agenus, Clovis, Clinical Care Options, Medscape/WebMD, Med Learning, I3Health, CMR Institute, Global Learning Initiative/Prova, OncLive, Targeted Oncology, Research to Practice, GOG Foundation, CEC Oncology, Clovis, Eisai, Merck, AstraZeneca, GSK, ImmunoGen, BioNTech, Daiichi Sankyo, EMD Serono, and Myriad, research funding from Clovis, Eisai, Immunogen, Merck, Beigene, Tempus, Natera, and AstraZeneca, and unpaid leadership roles with Society of Gynecologic Oncology, NRG Oncology Developmental therapeutics committee, and IGCS Education360. All other authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The NCCN Guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer provide multidisciplinary diagnostic workup, staging, and treatment recommendations for this disease. These NCCN Guidelines Insights detail how the evolution of the use of PARP inhibitors as maintenance and single-agent regimens for the treatment of ovarian cancer informed panel recommendations in the guidelines.

Paget's Disease of the Vulva is a relatively rare condition with a high rate of recurrence. Extensive work-up and treatment is warranted as lesions have the capacity to become invasive and can be associated with underlying malignancy. First line therapy includes surgical resection. For those that are not surgical candidates or who do not desire surgical intervention, non-surgical management options include topical therapy with imiquimod. Unfortunately, irritating side effects often results in poor treatment compliance and premature discontinuation limiting efficacy. Here we present a unique case of extensive, recurrent vulvar Paget's disease with excellent response to a combination therapy of imiquimod and Silver Sulfadiazine. To the best of our knowledge, this is the first documented case illustrating the utility of non-surgical management with combination therapy with topical imiquimod and Silver Sulfadiazine for treatment in patients who do not desire surgical intervention., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Floor Backes: Advisory boards/consulting: Merck, Eisai, ImmunoGen, AstraZeneca, EMD Serono, BioNTech, Daiichi Sankyo. Research funding: Merck, Eisai, ImmunoGen, AstraZeneca, Tempus, Natera., (© 2024 Published by Elsevier Inc.)

Introduction: Racial and ethnic disparities in gynecologic cancer care have been documented. Treatment at academic facilities is associated with improved survival, yet no study has examined independent associations between race and ethnicity with facility type among gynecologic cancer patients., Materials & Methods: We used the National Cancer Database and identified 484,455 gynecologic cancer (cervix, ovarian, uterine) patients diagnosed between 2004 and 2020. Facility type was dichotomized as academic vs. non-academic, and we used logistic regression to estimate multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) between race and ethnicity and facility type. Secondarily, we examined joint effects of race and ethnicity and facility type on overall survival using Cox proportional hazards regression., Results: We observed higher odds of treatment at academic (vs. non-academic) facilities among American Indian/Alaska Native (OR = 1.42, 95% CI = 1.28-1.57), Asian (OR = 1.64, 95% CI = 1.59-1.70), Black (OR = 1.69, 95% CI = 1.65-1.72), Hispanic (OR = 1.70, 95% CI = 1.66-1.75), Native Hawaiian/Pacific Islander (OR = 1.74, 95% CI = 1.57-1.93), and other race (OR = 1.29, 95% CI = 1.20-1.40) patients compared with White patients. In the joint effects survival analysis with White, academic facility-treated patients as the reference group, Asian, Hispanic, and other race patients treated at academic or non-academic facilities had improved overall survival. Conversely, Black patients treated at academic facilities [Hazard Ratio (HR) = 1.10, 95% CI = 1.07-1.12] or non-academic facilities (HR = 1.19, 95% CI = 1.16-1.21) had worse survival., Discussion: Minoritized gynecologic cancer patients were more likely than White patients to receive treatment at academic facilities. Importantly, survival outcomes among patients receiving care at academic institutions differed by race, requiring research to investigate intra-facility survival disparities., Competing Interests: Declaration of competing interest Dr. Plascak reports honoraria payments from National Comprehensive Cancer Network and North American Association of Central Cancer Registries. Dr. Backes reports personal fees from Agenus, CEC Oncology, Clovis, Eisai, Merck, AstraZeneca, GSK, ImmunoGen, BioNTech, Daiichi Sankyo, EMD Serono, and Myriad and research funding from Clovis, Eisai, Immunogen, Merck, Beigene, Tempus, and Natera. All other authors have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Advanced-stage endometrial and cervical cancers are associated with poor outcomes despite contemporary advances in surgical techniques and therapeutics. Recent clinical trial results have led to a shift in the treatment paradigm for both malignancies, in which immunotherapy is now incorporated as the standard of care up front for most patients with advanced endometrial and cervical cancers as the standard of care. Impressive response rates have been observed, but unfortunately, a subset of patients do not benefit from immunotherapy, and survival remains poor. Continued preclinical research and clinical trial development are crucial for our understanding of resistance mechanisms to immunotherapy and maximization of therapeutic efficacy. In this setting, syngeneic models are preferred over xenograft models as they allow for the evaluation of the tumor-immune interaction in an immunocompetent host, most closely mimicking the tumor-immune interaction in patients with cancer. Unfortunately, significant disparities exist about syngeneic models in gynecologic malignancy, in which queries from multiple large bioscience companies confirm no commercial availability of endometrial or cervical cancer syngeneic cell lines. Published data exist about the recent development of several endometrial and cervical cancer syngeneic cell lines, warranting further investigation. Closing the disparity gap for preclinical models in endometrial and cervical cancers will support physician scientists, basic and translational researchers, and clinical trialists who are dedicated to improving outcomes for our patients with advanced disease and poor prognosis., (©2024 American Association for Cancer Research.)

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/policies/article-withdrawal). This article has been retracted at the request of the Authors. The authors have independently identified an error in the formula that was utilized to calculate the Quality Adjusted Life Years which invalidates the data and the conclusion of the paper. The authors have contacted the journal requesting to retract the article. Apologies are offered to the readers of the journal for any confusion or inconvenience that may have resulted from the publication of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The use of a platinum doublet for the treatment of platinum-sensitive epithelial ovarian cancer (EOC) recurrence is well established. The impact of the non‑platinum chemotherapy used as part of a platinum doublet on PARP inhibitor (PARPi) and platinum sensitivity it not known. We aimed to describe oncologic outcomes in cases of recurrent EOC receiving PARPi as maintenance therapy based on preceding platinum doublet., Methods: Retrospective study of patients with platinum-sensitive recurrent ovarian, fallopian tube or primary peritoneal cancer treated with platinum doublet followed by maintenance PARPi from 1/1/2015 and 1/1/2022. Comparisons were made between patients receiving carboplatin + pegylated liposomal doxorubicin (CD) versus other platinum doublets (OPDs). Descriptive statistics, Kaplan-Meier and univariate survival analyses were performed., Results: 100 patients received PARPi maintenance following a platinum doublet chemotherapy regimen for platinum-sensitive recurrence. 25/100 (25%) received CD and 75/100 (75%) received OPDs. Comparing CD and OPDs, median progression-free survival was 8 versus 7 months (p = 0.26), median time to platinum resistance was 15 versus 13 months (p = 0.54), median OS was 64 versus 90 months (p = 0.28), and median OS from starting PARPi was 25 versus 26 months (p = 0.90), respectively., Conclusions: Using pegylated liposomal doxorubicin as part of a platinum doublet preceding maintenance PARPi for platinum-sensitive recurrence does not seem to hasten PARPi resistance or platinum resistance compared to OPDs. Although there was a non-significant trend towards increased OS among patients who received a platinum doublet other than CD prior to PARPi, the OS from PARPi start was similar between groups. Given the retrospective nature of this study and small study population, further research is needed to evaluate if the choice of platinum doublet preceding PARPi maintenance impacts PARPi resistance, platinum resistance and survival., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

At first recurrence, platinum-sensitive ovarian cancer (PSOC) is frequently treated with platinum-based chemotherapy doublets plus bevacizumab, then single-agent bevacizumab. Most patients' disease progresses within a year after chemotherapy, emphasizing the need for novel strategies. Mirvetuximab soravtansine-gynx (MIRV), an antibody-drug conjugate, comprises a folate receptor alpha (FRα)-binding antibody and tubulin-targeting payload (maytansinoid DM4). In FRα-high PSOC, MIRV plus bevacizumab previously showed promising efficacy (objective response rate, 69% [95% CI: 41-89]; median progression-free survival, 13.3 months [95% CI: 8.3-18.3]; median duration of response, 12.9 months [95% CI: 6.5-15.7]) and safety. The Phase III randomized GLORIOSA trial will evaluate MIRV plus bevacizumab vs. bevacizumab alone as maintenance therapy in patients with FRα-high PSOC who did not have disease progression following second-line platinum-based doublet chemotherapy plus bevacizumab. Clinical Trial Registration : ClinicalTrials.gov ID: NCT05445778; GOG.org ID: GOG-3078; ENGOT.ESGO.org ID: ENGOT-ov76.

Importance: Racial and ethnic disparities in clinical trial enrollment are unjust and hinder development of new cancer treatments., Objective: To examine the association of race and ethnicity with clinical trial enrollment among women with endometrial, ovarian, or cervical cancer., Design, Setting, and Participants: This retrospective cohort study used data from the National Cancer Database, a hospital-based cancer registry, and the Surveillance, Epidemiology, and End Results Program (SEER), a population-based cancer registry. Population-based race and ethnicity-specific proportions for each cancer site were derived from SEER. Participants included women with an endometrial, ovarian, or cervical cancer diagnosed from 2004 to 2019. Analyses were performed from February 2 to June 14, 2023., Exposure: Race and ethnicity were categorized as American Indian/Alaska Native, Asian, Black, Hispanic (any race), Native Hawaiian/Pacific Islander, White, and other (not defined in the National Cancer Database)., Main Outcomes and Measures: The primary outcomes were the odds of clinical trial enrollment and representation in clinical trials compared with the US population. Multivariable-adjusted logistic regression was used to estimate odds ratios (ORs) and 95% CIs for associations of race and ethnicity with clinical trial enrollment within the National Cancer Database sample. Participation-to-prevalence ratios (PPRs) according to diagnosis period (2004-2011 vs 2012-2019) were calculated by dividing the race and ethnicity-specific percentage of clinical trial participants in the study sample by the percentage of racial and ethnic groups in SEER., Results: Among 562 592 patients with gynecologic cancer (mean [SD] age at diagnosis, 62.9 [11.3] years), 1903 were American Indian/Alaska Native, 18 680 were Asian, 56 421 were Black, 38 145 were Hispanic, 1453 were Native Hawaiian/Pacific Islander, 442 869 were White, and 3121 were other race and ethnicity. Only 548 (<1%) were enrolled in clinical trials. Compared with White women, clinical trial enrollment was lower for Asian (OR, 0.44; 95% CI, 0.25-0.78), Black (OR, 0.70; 95% CI, 0.50-0.99), and Hispanic (OR, 0.53; 95% CI, 0.33-0.83) women. Compared with the US population, White women were adequately or overrepresented for all cancer types (PPRs ≥1.1), Black women were adequately or overrepresented for endometrial and cervical cancers (PPRs ≥1.1) but underrepresented for ovarian cancer (PPR ≤0.6), and Asian and Hispanic women were underrepresented among all 3 cancer types (PPRs ≤0.6)., Conclusions and Relevance: In this cohort of patients with gynecologic cancer, clinical trial enrollment was lower among certain minoritized racial and ethnic groups. Continued efforts are needed to address disparate clinical trial enrollment among underrepresented groups.

Objective: We sought to assess the impact of antibiotic (ABX) and proton-pump inhibitor (PPI) use on progression-free (PFS) and overall survival (OS) in patients treated with adjuvant platinum-based chemotherapy (PC) for endometrial cancer (EC)., Methods: A retrospective, single-institution cohort study of EC patients treated with ≥four cycles of adjuvant PC following surgical staging from 2014 to 2020. Demographics and clinicopathologic features, including ABX and PPI use, were compared using χ 2 and Fisher's exact tests. Univariate and multivariable analyses were performed, and survival outcomes were compared using the log-rank test., Results: Of 325 patients, 95 (29%) received ABX, and 80 (24.6%) received PPI. ABX were associated with decreased 3-year PFS (49.9% vs. 66%; p = 0.0237) but not 3-year OS (68.9% vs. 79.9%; p = 0.0649). ABX targeting gram-positive bacteria were associated with decreased 3-year PFS (21.2% vs. 66.0% vs. 55.4%; p = 0.0038) and 3-year OS (36.5% vs. 79.9% vs. 75.6%; p = 0.0014) compared to no ABX and other ABX, respectively. PPI use was associated with decreased 3-year PFS (46.9% vs. 66.0%; p = 0.0001) and 3-year OS (60.7% vs. 81.9%; p = 0.0041) compared to no PPI. On multivariable regression analysis controlling for confounders including stage, histology, grade, radiation, and co-morbidities, PPI use was independently associated with worse PFS (HR 1.96, 95% CI 1.25-3.08; p = 0.0041) and OS (HR 2.06, 95% CI 1.01-4.18, p = 0.04)., Conclusion: In this retrospective cohort study, we demonstrate that PPI use is independently associated with worse PFS and OS in patients with EC treated with PC. ABX use was associated with worse PFS on univariate analysis only. There is an unmet need to understand how PPI, ABX, and, potentially, the microbiome impact the effectiveness of chemotherapy in EC patients., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest related to the content of this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: We sought to provide a contemporary report on stage IVB endometrial carcinoma (2009 FIGO criteria) and applied the 2023 FIGO staging criteria to this population., Methods: Retrospective review of patients who underwent cytoreduction for stage IVB endometrial carcinoma (2009 FIGO criteria) from 2014 to 2020 was performed. Demographics, clinicopathologic factors, and outcomes were recorded. Disease burden and distribution were determined by imaging, operative notes, and pathology reports. Patients were re-staged according to 2023 FIGO staging criteria. Categorical variables were compared using χ 2 or Fisher's exact test, and Kaplan-Meier curves compared survival outcomes using the log-rank test., Results: Eighty-eight cases were included. Most patients (63.6%) were not suspected to have stage IVB (2009 FIGO criteria) disease prior to surgery. Seventy-two percent of patients underwent primary cytoreduction, and 12 (19%) were suboptimal. Median progression-free survival (PFS) was 12 months (95% CI 10-16 months), and median overall survival (OS) was 38 months (95% CI 19-61 months). Degree of cytoreduction (p = 0.0101) and pelvic-confined metastatic disease (p = 0.0149) were significant prognostic factors, while distant metastases were not associated with worse outcomes. For those patients who underwent primary cytoreduction, number (p = 0.0453) and diameter (p = 0.0192) of tumor deposits were associated with PFS. When 2023 FIGO staging criteria were applied, 58% of patients underwent change in stage, and 8% did not meet criteria for complete staging. PFS was significantly different based on 2023 FIGO staging (p = 0.0307); a trend in OS was also noted (p = 0.0550)., Conclusion: Stage IVB endometrial carcinoma (2009 FIGO criteria) encompasses a diverse cohort of patients, where certain clinicopathologic features, tumor burden, and degree of cytoreduction are associated with outcomes. The 2023 FIGO staging criteria significantly improves our ability to risk-stratify patients., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest related to the content of this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Melanomas from gynecologic sites (MOGS) are rare and have poor survival. MicroRNAs (miRs) regulate gene expression and are dysregulated in cancer. We hypothesized that MOGS would display unique miR and mRNA expression profiles. The miR and mRNA expression profile in RNA from formalin fixed, paraffin embedded vaginal melanomas (relative to vaginal mucosa) and vulvar melanomas (relative to cutaneous melanoma) were measured with the Nanostring Human miRNA assay and Tumor Signaling mRNA assay. Differential patterns of expression were identified for 21 miRs in vaginal and 47 miRs in vulvar melanoma (fold change >2, p<0.01). In vaginal melanoma, miR-145-5p (tumor suppressor targeting TLR4, NRAS) was downregulated and miR-106a-5p, miR-17-5p, miR-20b-5p (members of miR-17-92 cluster) were upregulated. In vulvar melanoma, known tumor suppressors miR-200b-3p and miR-200a-3p were downregulated, and miR-20a-5p and miR-19b-3p, from the miR-17-92 cluster, were upregulated. Pathway analysis showed an enrichment of "proteoglycans in cancer". Among differentially expressed mRNAs, topoisomerase IIα (TOP2A) was upregulated in both MOGS. Gene targets of dysregulated miRs were identified using publicly available databases and Pearson correlations. In vaginal melanoma, suppressor of cytokine signaling 3 (SOCS3) was downregulated, was a validated target of miR-19b-3p and miR-20a-5p and trended toward a significant inverse Pearson correlation with miR-19b-3p (p = 0.093). In vulvar melanoma, cyclin dependent kinase inhibitor 1A (CDKN1A) was downregulated, was the validated target of 22 upregulated miRs, and had a significant inverse Pearson correlation with miR-503-5p, miR-130a-3p, and miR-20a-5p (0.005 < p < 0.026). These findings support microRNAs as mediators of gene expression in MOGS., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 DiVincenzo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To determine the safety and feasibility of same-day discharge (SDD) following minimally invasive hysterectomy (MIH) for elderly patients and to evaluate associations between age, frailty, and postoperative outcomes., Methods: Retrospective review was conducted of patients aged ≥ 70 who underwent MIH within a single gynecologic oncology institution from 2018 to 2020. Demographics, peri -operative factors, postoperative complications, and 30-day readmission rates were collected. Frailty was determined by an 11-point modified frailty index ≥ 2. Outcomes were compared between SDD and observation groups using Fisher's exact and Wilcoxon rank-sum tests., Results: Of 169 patients included in the analysis, 8.9% (n = 15) underwent SDD, and 91.1% (n = 154) were admitted for OBS following MIH. Demographics, peri -operative factors, and frailty rates (33% SDD vs 43.5% observation; p = 0.59) were similar between groups. 86.7% (n = 13) of SDD cases were completed before 12PM, and none were completed after 6PM. No SDD patients had early post-operative complications or hospital readmissions. Early postoperative complications were diagnosed in 9 (5.8%) patients admitted for OBS, and the 30-day hospital readmission rate for patients who underwent OBS was 8.4% (n = 13). While elderly patients who met objective frailty criteria (n = 72) did not have a higher likelihood of early post-operative complications (44.4% vs 55.6%; p = 0.909), they did have a higher likelihood of ED visit within 30 days of discharge (15.3 vs 3.1%; p = 0.009), and a trend was noted toward a higher rate of 30-day hospital readmission (12.5% vs 4.1%; p = 0.080)., Conclusions: Elderly patients undergoing SDD following MIH did not have increased morbidity or mortality. Elderly patients who meet objective criteria for frailty, however, represent a more vulnerable population., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Objectives: To describe stage, treatment patterns, and survival for glassy cell carcinoma of the cervix (GCCC), a poorly understood rare tumor., Methods: Clinical data and survival were compared between GCCC and more common histologic types using the National Cancer Database (NCDB) from 2004 to 2017. A retrospective review of GCCC cases at our institution from 2012 to 2020 was simultaneously performed with staging updated according to 2018 FIGO staging. Descriptive statistics and survival analyses were performed, and outcomes compared to historical references., Results: 143/89,001 (0.16%) NCDB cervical cancer cases were GCCC. Compared to other histologies, GCCC cases were younger, with 74.8% diagnosed before age 50. Stage distribution was similar. Stage I cases were less commonly treated with surgery alone (19/69, 27%). 79.4% of locally advanced (stage II-IVA) cases were treated with definitive chemoradiation. GCCC demonstrated worse OS for early-stage and locally-advanced disease. No survival differences were observed for patients with stage IVB disease. Our institutional review identified 14 GCCC cases. Median age at diagnosis was 34 years. All nine early-stage cases underwent radical hysterectomy. Adjuvant radiation was given for cases meeting Sedlis criteria (4/9, 44%). All five advanced stage cases were stage IIIC and received definitive chemoradiation. Recurrence rate was 0% (0/9) for early-stage and 60% (3/5) for advanced-stage cases. 3-year PFS was 100% for early-stage and 40% for advanced-stage. 3-year OS was 100% for early-stage and 60% for advanced-stage GCCC., Conclusions: GCCC presents at earlier ages than other cervical cancer histologic types. Although NCDB showed worse OS, our more contemporary institutional review, which incorporates updated staging and newer treatment modalities found outcomes more similar to historical references of more common histologic subtypes., (Published by Elsevier Inc.)

Background: Uterine cancers are associated with a high risk for venous thromboembolisms. The American Society of Clinical Oncology practice guidelines recommend that all patients undergoing pelvic surgery for cancer should receive extended pharmacologic thromboprophylaxis with the duration being dependent on risk. However, risk stratification for patients with uterine cancer is not clearly defined. The Caprini score is the most widely used risk assessment model but it has been found to have limited use in the gynecologic oncology population. A modified Caprini score has been explored in other populations. The Khorana score is an additional risk assessment model that has not been studied in this context., Objective: Our objective was to evaluate the ability of a modified Caprini model and the Khorana score to risk stratify patients with uterine cancer for postoperative venous thromboembolisms within 90 days of surgery., Study Design: Following institutional review board approval, a retrospective cohort study was performed, and all patients with uterine cancer who underwent a hysterectomy over a 4-year period were included. The Caprini and Khorana scores were calculated for each patient. The Caprini score cutoff for highest risk was evaluated at ≥7, ≥8, and ≥9 (modified Caprini) and the Khorana score cutoff was evaluated at ≥2 and ≥3. To determine the prognostic use of each score and other clinico-pathologic criteria related to the development of a venous thromboembolism, univariate analyses were performed using independent t tests, chi-square tests, or Fisher's exact tests; a multivariate analysis was performed using logistic regression., Results: A total of 954 patients were included. The rate of venous thromboembolism development was 1.7% (16/954). A minimally invasive surgical approach was used in 90.5% (863/954) of patients. The mean Caprini score for patients with a venous thromboembolism was 10.3 compared with 8.1 for patients without a venous thromboembolism (95% confidence interval, 1.17-3.33; P<.0001). The mean Khorana score for the venous thromboembolism group was 2.4 vs 1.9 for those without (95% confidence interval, 0.04-0.82; P=.03). Both the Caprini and Khorana scores were found to be associated with venous thromboembolisms, but only a Caprini score with a cutoff of ≥8 or ≥9 was statistically significant (risk ratio, 31.25; 95% confidence interval, 1.88-519.49; risk ratio, 4.59; 95% confidence interval, 1.49-14.13, respectively), with high accuracy based on the area under the curve (0.75 and 0.68, respectively). Of the minimally invasive subgroup, 11.7% (101/863) of patients had same-day discharge with no postoperative thromboprophylaxis; none of these patients developed venous thromboembolisms. Despite extended prophylaxis among the laparotomy patients (30 days), the rate of venous thromboembolisms was more than 3 times that of the minimally invasive group (5.49% vs 1.7%). Advanced tumor stage and leukocytosis were noted to be independent risk factors for venous thromboembolisms., Conclusion: Our study suggests that using a modified Caprini score could help to identify the highest-risk patients who would benefit from prolonged thromboprophylaxis, could reduce the incidence of postoperative venous thromboembolisms, and could minimize the cost and harm of overtreatment. These findings need to be validated in a prospective manner, and further research is needed to determine the optimal duration of therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: We sought to evaluate the contribution of mismatch repair (MMR) status to traditional risk stratification algorithms used to predict nodal involvement and recurrence in a large single-institution cohort., Methods: Endometrioid endometrial cancer (EC) cases from 2014-2020 were evaluated. MMR immunohistochemistry (IHC) was performed universally. Uterine factors assessed in the Mayo criteria were used to retrospectively classify patients as low or high risk for lymphatic spread. Patients were classified according to risk for recurrence using GOG 99 and PORTEC criteria. Associations were evaluated using chi-square and t-tests and contributing factors assessed using logistic regression models., Results: 1,514 endometrioid EC were evaluated; 392 (25.9%) were MMR (MMR) deficient of which 80.4% of MMR defects were associated with epigenetic silencing of MLH1 . Epigenetic MMR defects were significantly more likely to be high risk for lymph node (LN) metastasis based on Mayo criteria (74.9% vs 60.6%, p =<0.001) and with the presence of LN metastasis (20.3 vs 10.5%, p =0.003) compared to MMR proficient tumors. Tumors with epigenetic MMR defects were significantly more likely to be classified as high or high intermediate risk using GOG99 and PORTEC criteria. Furthermore, cases with epigenetic MMR defects classified as low or low intermediate risk were significantly more likely to recur (GOG99 p =0.013; PORTEC p =0.008) and independently associated with worse disease-free survival (DFS). MMR status was found to be independently associated with worse DFS (HR 1.90; 95% CI 1.34-2.70; p =0.003) but not overall survival., Conclusion: While MMR deficient EC has been associated with poor prognostic features in prior reports; we demonstrate that only epigenetic MMR defects have poorer outcomes. Epigenetic MMR defect were independently associated with lymph node metastasis after controlling for risk criteria. Epigenetic MMR deficiency was found to be an independent predictor of recurrence beyond the factors considered in traditional risk stratification algorithms. Traditional uterine-based risk stratification algorithms may not fully reflect the risk for recurrence in MMR deficient tumors. Consideration should be given to implementing MMR status and MLH1 hypermethylation alongside traditional risk stratification algorithms. Performing MMR IHC on preoperative pathologic specimens may aid in risk stratification and patient counseling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Riedinger, Brown, Haight, Backes, Cohn, Goodfellow and Cosgrove.)

Effective second-line treatment options for patients with recurrent ovarian clear cell carcinoma (OCCC) are limited. This case series sought to report tumor characteristics and oncologic outcomes in a small group of patients treated with combination lenvatinib and pembrolizumab. A retrospective analysis of patients with ovarian clear cell carcinoma treated with combination lenvatinib and pembrolizumab at a single institution was performed. Patient and tumor characteristics were collected including demographics and germline/somatic testing. Clinical outcomes were also evaluated and reported. Three patients with recurrent OCCC were included in the study. The median age of patients was 48 years old. All patients had platinum-resistant disease and had received 1-3 prior lines of therapy. The overall response rate was 100% (3/3). Progression-free survival ranged from 10 months to not-yet-reached. One patient remains on treatment, while the other two died of disease with overall survival of 14 and 27 months. Combination lenvatinib-pembrolizumab demonstrated favorable clinical response in these patients with platinum-resistant, recurrent, ovarian clear cell carcinoma., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (©2023PublishedbyElsevierInc.)

Objective: To determine the recurrence rate and survival among early-stage epithelial ovarian cancer cases considering homologous recombination deficiency (HRD) status., Methods: Single institution retrospective study of stage I/II EOC patients from 2017 to 2020. HRD was defined as evidence of germline or somatic BRCA mutation, or loss of heterozygosity (LOH)/genomic instability (GIS) as determined by companion diagnostic tests. Kaplan-Meier analyses were performed., Results: 89 stage I/II cases were included. 4/89 (4.5%) had a germline BRCA1/2 mutation, 8 (9%) were germline negative but had a somatic BRCA mutation, and 8 (9%) were BRCA wild-type but had evidence of LOH/GIS on somatic testing; these 20/89 (22%) cases comprised the HRD group. The remaining tumors were confirmed homologous recombination proficient (HRP, 35/89, 39%) or homologous recombination unknown (HRU, 34/89, 38%). The overall recurrence rate was 33/89 (37%). There were more recurrences among HRD cases (14/20, 70%) compared to HRP/HRU cases (19/69, 27.5%, p = 0.0012). Median Recurrence-Free Survival (RFS) was 35 months for HRD cases and 225 months for HRP/HRU cases (p = 0.001). At 2 years, there were 60% HRD cases and 88% HRP/HRU cases recurrence-free. At 5 years there were 29% HRD and 69% HRP/HRU cases recurrence-free (p = 0.001)., Conclusions: Despite a high rate of complete surgical staging and six cycles of adjuvant chemotherapy, recurrence rate was high in this early-stage cohort. Higher recurrence rates were seen in the HRD group, however these data are likely biased by the clinical practice of tumor testing primarily at the time of recurrence rather than the upfront setting. RFS was significantly lower for HRD cases., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Backes reports grants and personal fees from Clovis, Eisai, Merck, grants from Immunogen, personal fees from Agenus, AstraZeneca, Genentech, GlaxoSmithKline, all outside the submitted work. Dr. Bixel reports personal fees for participation on advisory board for Merck and data safety monitoring board for GOG3043 and the ROCC Trial. Dr. Copeland reports personal fees from Celsion Corporation, Corcept Therapeutics, Elevar Therapeutics, grants and personal fees from GSK, personal fees from Myriad Genetics, Inc, Rubius Therapeutics, Sorrento Therapeutics, Tarveda Therapeutics, Toray Industries, Inc, grants from Abbvie, Advaxis, Agenus, Ajinomoto, Array BioPharm, AstraZeneca, Bristol Myers Squbb, Clovis Oncology, Deciphera Parma, Eisai, EMD Serono Inc, ERGOMED Clinical Research, Exelixis, Genentech/Roche, Genmab, Hoffman-LaRoche, grants and personal fees from Immunogen, grants from Incyte Corporation, Iovance Biotherapeutics, InVentive Health Clinical, Jansen R&D, Leap Therapeutics, Ludwig Institute for Pharmaceuticals, Merck, Mersana Therapeutics, Novocure, Novartis Pharmaceuticals, OncoQuest, PRA International, Regeneron Pharmaceuticals, Seattle Genetics, Serono, Sutro Biopharm, Tesaro (GSK), Arcus Biosciences, Sumitomo Dainippon Pharma Oncology, Cerulean Pharma, Karyopharm, BeiGene USA, Ovagene, Pfizer, Pharma Mar USA, Precision Therapeutics, Sanofi, Stemcentrx, TRACON Pharm, Verastem, personal fees from VBL Therapeutics, OncoNova, Inx Med, Luzsana Biotechnology, all outside the submitted work. Dr. Cohn reports honoraria from UpToDate and Elsevier, Gynecologic Oncology. Dr. Cosgrove reports honoraria from AstraZeneca and GlaxoSmithKline, all outside the submitted work. Dr. O'Malley reports personal fees for consulting and/or advisory boards from AstraZeneca, Tesaro/GSK, BBI, Immunogen, Ambry, Janssen/J&J, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, GOG Foundation, Iovance Biotherapeutics, Myriad Genetics, Eisai, Agenus, Tarveda, Merck, SeaGen, Novartis, Mersana, Clovis, Rubius, Elevar; Research funding (all funding to institution): AstraZeneca, Tesaro/GSK, Immunogen, Janssen/J&J, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, VentiRx, Array Biopharma, EMD Serono, Ergomed, Ajinomoto, Ludwig Cancer Research, Stemcentrx, CERULEAN PHARMA, GOG Foundation, NCI, BMS, Serono Inc., Yale University, New Mexico Cancer Care Alliance, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, PRA International, Eisai, Agenus, Merck, GenMab, SeaGen, Mersana, and Clovis; leadership or fiduciary role for BOD – GOG Foundation, and Editorial Board for Gynecologic Oncology. Ms. Senter reports consulting fees and honoraria from AstraZeneca and GlaxoSmithKline and she serves on the board of trustees for the Association of Community Cancer Centers.]., (© 2023 The Author(s).)

Hormonal therapy has long been a treatment modality for recurrent endometrial cancer. It is appealing for patients with low-grade, slow-growing tumors or in patients for which other treatment types may be too toxic. Hormonal therapy is well tolerated and has response rates ranging from 9 to 33%. Hormonal treatment options take advantage of the estrogen-dependent molecular pathways in endometrial cancers. Current options for hormonal therapies include progesterone therapy (medroxyprogesterone acetate and megestrol acetate) as a single agent or in combination and agents that target the estrogen pathway. Aromatase inhibitors have had modest single-agent activity, but synergistic effects have been found when used in combination with targeted therapy including mTOR inhibitors and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Molecular profiling of endometrial cancers has begun to help individualize treatments. This review will report on existing data and ongoing trials investigating novel hormonal therapy agents.

Objectives: To determine whether morbid obesity should serve as an independent factor in the decision for same day discharge following minimally invasive hysterectomy., Methods: Retrospective review was performed of patients with BMI ≥ 40 who underwent minimally invasive hysterectomy within a single comprehensive cancer center between January 2018 - August 2020. Demographics, perioperative factors, post-operative monitoring, complications, and readmissions were compared between patients who underwent same day discharge and overnight observation using Fisher's exact tests and Wilcoxon rank-sum tests., Results: 374 patients with BMI ≥ 40 were included. Eighty-three (22.2%) patients underwent same day discharge, and 291 (77.8%) patients underwent overnight observation. Factors associated with increased likelihood of same day discharge included younger age (median age 53 vs 58; p = 0.001), lower BMI (median BMI 45 vs 47; p = 0.005), and fewer medical co-morbidities (Charlson Co-Morbidity Index 2 vs 3; p < 0.001). On multivariate regression analysis, frailty (OR 2.16 [1.14-4.11], p = 0.019) and surgical completion time after 12 PM (OR 3.67 [2.16-6.24], p < 0.001) were associated with increased risk of overnight observation. Few patients admitted for routine overnight observation required medical intervention (n = 14, 4.8%); most of these patients were frail (64.3%). The overall hospital readmission rate within 30 days of discharge was 3.2% (n = 12), with no patients discharged on the day of surgery being readmitted., Conclusions: Morbid obesity alone should not serve as a contraindication to same day discharge following minimally invasive hysterectomy. Admission for observation was associated with low rates of clinically meaningful intervention, and patients who underwent same day discharge were not at increased risk of adverse outcome., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest including financial, personal, or other relationships with other people or organizations within two years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Gynecologic cancers are associated with a high risk of venous thromboembolism (VTE). The Khorana score is a validated tool to assess risk of VTE in cancer patients. The purpose of this study is to determine if the Khorana score can be used as a risk stratification tool for VTE in patients with uterine cancer undergoing chemotherapy., Methods: A retrospective cohort study of patients with newly diagnosed uterine cancer receiving chemotherapy over a 4-year period was conducted. The patients were stratified based on their Khorana score as well as their chemotherapy sequence, neoadjuvant or definitive versus adjuvant., Results: A total of 276 patients were included: 40 received neoadjuvant or definitive, 236 adjuvant chemotherapy. Most patients had advanced stage disease (64.5%). 18 (6.5%) patients developed VTE within 180 days of initiating chemotherapy. High Khorana score was associated with a non-significant increase in VTE (K ≥ 2 OR 1.17, CI 0.40-3.39, K ≥ 3 OR 1.69, CI 0.61-4.69) but had poor predictive accuracy based on area under the curve (K ≥ 2 0.51, K ≥ 3 0.55). The VTE rate was higher in the neoadjuvant/definitive chemotherapy group to adjuvant (12.5% vs 5.5%, p = 0.11). While the former group had a higher average Khorana score (2.35 vs 1.93, p = 0.0048), this was not predictive of VTE., Conclusions: While validated in other cancer types, the Khorana score was found to be a poor predictor of VTE in patients with uterine cancer. The use of the Khorana score to guide routine thromboprophylaxis in these patients should be used with caution and further investigation is warranted., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Backes reports grants and personal fees from Clovis, Eisai, Merck, grants from Immunogen, personal fees from Agenus, AstraZeneca, Genentech, GlaxoSmithKline, all outside the submitted work. Dr. Copeland reports personal fees from Celsion Corporation, Corcept Therapeutics, Elevar Therapeutics, grants and personal fees from GSK, personal fees from Myriad Genetics, Inc, Rubius Therapeutics, Sorrento Therapeutics, Tarveda Therapeutics, Toray Industries, Inc, grants from Abbvie, Advaxis, Agenus, Ajinomoto, Array BioPharm, AstraZeneca, Bristol Myers Squbb, Clovis Oncology, Deciphera Parma, Eisai, EMD Serono Inc, ERGOMED Clinical Research, Exelixis, Genentech/Roche, Genmab, Hoffman-LaRoche, grants and personal fees from Immunogen, grants from Incyte Corporation, Iovance Biotherapeutics, InVentive Health Clinical, Jansen R&D, Leap Therapeutics, Ludwig Institute for Pharmaceuticals, Merck, Mersana Therapeutics, Novocure, Novartis Pharmaceuticals, OncoQuest, PRA International, Regeneron Pharmaceuticals, Seattle Genetics, Serono, Sutro Biopharm, Tesaro (GSK), Arcus Biosciences, Sumitomo Dainippon Pharma Oncology, Cerulean Pharma, Karyopharm, BeiGene USA, Ovagene, Pfizer, Pharma Mar USA, Precision Therapeutics, Sanofi, Stemcentrx, TRACON Pharm, Verastem, personal fees from VBL Therapeutics, OncoNova, Inx Med, Luzsana Biotechnology, all outside the submitted work. Dr. Cosgrove reports honoraria from UpToDateConsulting and personal fees from Agenus, all outside the submitted work. Dr. O'Malley reports personal fees for consulting and/or advisory boards from AstraZeneca, Tesaro/GSK, BBI, Immunogen, Ambry, Janssen/J&J, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, GOG Foundation, Iovance Biotherapeutics, Myriad Genetics, Eisai, Agenus, Tarveda, Merck, SeaGen, Novartis, Mersana, Clovis, Rubius, Elevar; Research funding (all funding to institution): AstraZeneca, Tesaro/GSK, Immunogen, Janssen/J&J, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, VentiRx, Array Biopharma, EMD Serono, Ergomed, Ajinomoto, Ludwig Cancer Research, Stemcentrx, Cerulean Pharma, GOG Foundation, NCI, BMS, Serono Inc., Yale University, New Mexico Cancer Care Alliance, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, PRA International, Eisai, Agenus, Merck, GenMab, SeaGen, Mersana, and Clovis; leadership or fiduciary role for BOD – GOG Foundation, and Editorial Board for Gynecologic Oncology. None of the authors have a significant conflict of interest related to the current study., (© 2023 The Authors. Published by Elsevier Inc.)

Background: With the increasing rates of same-day discharge following minimally invasive surgery for endometrial cancer, the need for and value of routine postoperative testing is unclear., Objective: This study aimed to determine whether routine postoperative laboratory testing following minimally invasive hysterectomy for endometrial cancer leads to clinically significant changes in postoperative care., Study Design: This was a single-institution retrospective cohort study of patients undergoing minimally invasive hysterectomy for endometrial cancer by a gynecologic oncologist between June 2014 and June 2017. Patient demographics, preoperative comorbidities, operative and postoperative data, and pathologic findings were manually extracted from the patients' medical records. The financial burden of laboratory testing was computed using hospital-level cost data., Results: Of the 649 women included in the analysis, most (91.4%) were White, with a mean age of 61 years, and mean body mass index of 38.0 kg/m 2 . The most common comorbidities were diabetes mellitus (31.9%, n=207), chronic pulmonary disease (7.9%, n=51), and congestive heart failure (3.2%, n=21). Median operative time was 151 minutes (range, 61-278), and median estimated blood loss was 100 mL (range, 10-1500). Most patients (68.6%, n=445) underwent lymphadenectomy. All patients had postoperative laboratory tests ordered: 100% complete blood count, 99.7% chemistry, 62.9% magnesium, 46.8% phosphate, 37.4% calcium, and 1.2% liver function tests. Twenty-six patients (4.0%) had a change in management owing to postoperative laboratory test results. Of these 26 women, 88% experienced a change in clinical status that would have otherwise prompted testing. Only 3 (0.5% of entire cohort) were asymptomatic: 1 received a blood transfusion for asymptomatic anemia, and the other 2, who did not carry a diagnosis of diabetes mellitus, had interventions for hyperglycemia. On univariable analysis, peripheral and cerebrovascular disease, diabetes mellitus with end-organ damage, and a Charlson Comorbidity Index of ≥3 were associated with increased odds of change in management; these were not significant on multivariable analysis. Routine postoperative laboratory evaluation in this cohort increased hospital costs by $292,000., Conclusion: Routine postoperative laboratory tests are unlikely to lead to significant changes in management for women undergoing minimally invasive hysterectomy for endometrial cancer, and may increase cost without providing a discernible clinical benefit. In the setting of strict postoperative guidelines, laboratory tests should be ordered when clinically indicated rather than as part of routine postoperative management for women undergoing minimally invasive hysterectomy for endometrial cancer., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To examine patients with confirmed endometrial cancer recurrence; evaluate patterns, presentation, and mode of diagnosis., Study Design: A retrospective review of women with endometrial cancer diagnosis between 2014 and 2020. Disease recurrences were evaluated. Medical records were reviewed focusing on presentation at time of recurrence. Relationships were assessed using χ2, Fisher's exact test, t-test, and Wilcoxon test. The Kaplan-Meier product limit was used to estimate survival. Multiple logistic regression analysis was used to assess the impact of covariates., Results: Endometrial cancer recurrence was identified in 201 (11.7%) patients. Sixty percent (120/201) of patients presented with symptoms. Pain was the most common presenting symptom (23.4%, 47/201) and bleeding was reported in <14% (28/201). Patients with symptomatic presentation were less likely to be able to receive treatment for their recurrent disease (76.7% vs 91.3%, p = 0.005). Asymptomatic pelvic exam diagnosed recurrence in 13.4% (27/201) and was more common in patients initially diagnosed with early-stage disease (66.7% vs 34.5% p = 0.001) of endometrioid histology (66.7% vs 36.8%, p = 0.003) without prior adjuvant therapy (48.2% vs 17.9%, p = 0.001). More than1/3 of diagnoses were made by providers outside of the oncologic care team., Conclusion: The majority of women with recurrent endometrial cancer were symptomatic and pain is a common complaint associated with disease recurrence. Patients with symptomatic presentation of disease recurrence were less likely to receive treatment for recurrent disease but this did not result in an overall survival (OS) difference. Given the rising mortality rate of endometrial cancer further work is needed to develop multidisciplinary surveillance strategies that will enable meaningful treatment of disease recurrence., Competing Interests: Declaration of Competing Interest The authors have no relevant conflict of interest impacting the content of this manuscript., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

Epithelial ovarian cancer is the most lethal malignancy of the female reproductive tract. A healthy ovary expresses both Estrogen Receptor α (ERα) and β (ERβ). Given that ERα is generally considered to promote cell survival and proliferation, thereby, enhancing tumor growth, while ERβ shows a protective effect against the development and progression of tumors, the activation of ERβ by its agonists could be therapeutically beneficial for ovarian cancer. Here, we demonstrate that the activation of ERβ using a newly developed ERβ agonist, OSU-ERb-12, can impede ovarian cancer cell expansion and tumor growth in an ERα-independent manner. More interestingly, we found that OSU-ERb-12 also reduces the cancer stem cell (CSC) population in ovarian cancer by compromising non-CSC-to-CSC conversion. Mechanistically, we revealed that OSU-ERb-12 decreased the expression of Snail, a master regulator of the epithelial-to-mesenchymal transition (EMT), which is associated with de novo CSC generation. Given that ERα can mediate EMT and facilitate maintenance of the CSC subpopulation and that OSU-ERb-12 can block the transactivity of ERα, we conclude that OSU-ERb-12 reduces the CSC subpopulation by inhibiting EMT in an ERα-dependent manner. Taken together, our data indicate that the ERβ agonist OSU-ERb-12 could be used to hinder tumor progression and limit the CSC subpopulation with the potential to prevent tumor relapse and metastasis in patients with ovarian cancer.

Objectives: The laparoscopic hysterectomy readmission score (LHRS) was created to identify patients for whom same day discharge (SDD) after minimally invasive hysterectomy (MIH) may not be advisable and includes diabetes, chronic obstructive pulmonary disease, disseminated cancer, chronic steroid use, bleeding disorder, length of surgery, and any postoperative complication prior to discharge. We evaluated the performance of the score at predicting readmission in a gynecologic oncology population, and additionally sought to determine if any factors known prior to surgery could replace those that are not known until the time of surgery (operative time and postoperative complication)., Methods: This was a single-institution retrospective cohort study of women undergoing robotic hysterectomy by a gynecologic oncologist in 2018. Associations between pre-operative, operative and post-operative factors and 30-day readmission, SDD and postoperative complications were assessed using logistic regression., Results: The 30-day readmission rate among the 423 women in the cohort was 4.5% and 1.9% in those undergoing SDD. Readmission rates by LHRS were: score 1 (4.9%), score 2 (7.8%), score 3 (13.6%), score 4 (16.7%). Patients with a LHRS of ≥3 had higher odds of readmission compared to those with a lower score (OR 4.20, p = 0.02). Infectious morbidity accounted for the majority of postoperative complications, emergency room visits and readmissions. We did not identify preoperative factors to replace the intra- and post-operative factors used in the score., Conclusions: The readmission rate following MIH is low, and a LHRS of ≥3 is associated with increased risk of readmission. Our findings support the applicability of the LHRS to a gynecologic oncology population; addressing risk factors for postoperative infection or closer follow up for patients with a LHRS ≥3 could reduce postoperative readmissions., Competing Interests: Declaration of Competing Interest Michelle Lightfoot has nothing to disclose. Ashley Felix has nothing to disclose. Erin Bishop has nothing to disclose. Alexa Henderson has nothing to disclose. Monica Vetter has nothing to disclose. Ritu Salani: investigation, resources, writing – reviewing and editing. David O'Malley reports personal fees and other from AstraZeneca, personal fees and other from Tesaro/GSK, personal fees and other from Immunogen, personal fees from Ambry, personal fees and other from Janssen/J&J, personal fees and other from Abbvie, personal fees and other from Regeneron, personal fees and other from Amgen, personal fees and other from Novocure, personal fees and other from Genentech/Roche, other from VentiRx, other from Array Biopharma, other from EMD Serono, other from Ergomed, other from Ajinomoto Inc., other from Ludwig Cancer Research, other from Stemcentrx, Inc., other from CERULEAN PHARMA, personal fees and other from GOG Foundation, other from Bristol-Myers Squibb Co, other from Serono Inc., other from TRACON Pharmaceuticals, other from Yale University, other from New Mexico Cancer Care Alliance, other from INC Research, Inc., other from inVentiv Health Clinical, personal fees and other from Iovance Biotherapeutics, Inc., other from PRA Intl, personal fees from Myriad Genetics, personal fees and other from Eisai, personal fees and other from Agenus, personal fees from Tarveda, personal fees and other from Merck, other from GenMab, personal fees and other from SeaGen, personal fees from Novartis, personal fees and other from Mersana, personal fees and other from Clovis, personal fees from Rubis, personal fees from Elevar, personal fees from Takeda, personal fees from Toray, personal fees from INXMED, personal fees and other from SDP Oncology (BBI), personal fees from Arquer Diagnostics, personal fees from Roche Diagnostics MSA, personal fees from Sorrento, outside the submitted work. Kristin Bixel reports grants from Intuitive, outside the submitted work; and Intuitive advisory board participant. David Cohn has nothing to disclose. Jeffrey Fowler has nothing to disclose. Floor Backes reports grants and personal fees from Eisai, grants and personal fees from Merck, grants from Immunogen, grants and personal fees from Clovis, personal fees from Agenus, personal fees from AstraZeneca, personal fees from Genentech, personal fees from GlaxoSmithKline, outside the submitted work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling., Patients and Methods: In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored., Results: Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009)., Conclusions: Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation., Competing Interests: Competing interests: SL has received honoraria from AstraZeneca, Merck, Eisai, GSK, and Roche. PAK has participated in Advisory Boards/Scientific Advisory Committees for Alkermes, AstraZeneca, Bayer, GSK, Merck, Pfizer, Tesaro, Vertex, and Repare; and has received institutional funding as Principal Investigator from AstraZeneca, Bayer, Eli Lilly, GSK, Merck, Merck KGaA, Pfizer, and Tesaro/GSK. BXW has no conflicts of interest related to this manuscript; financial disclosures that are not related: he has received honoraria from Tessa Therapeutics and AstraZeneca. MSB has no conflicts of interest related to this manuscript; financial disclosures that are not related: he has received institutional research support from Merck, Transgene, Pharmacyclics, Immune Design, Bristol Myers Squibb, Marker Therapeutics, Sorrento, Viewpoint Molecular Targeting, and Genentech; and is an Advisory Board member (unpaid) for TILT Biotherapeutics, Viewpoint Molecular Targeting, and Sorrento. SLG has received personal fees from AstraZeneca, Immunogen, Sermonix, Elvar Therapeutics, and GSK; and has received grants from AstraZeneca, AbbVie, Pfizer, Rigel, Iovance, Tesaro, Genentech/Roche, PharmaMar, and GSK; and has patents for Sermonix (US patent no. 10,905,659 and 10,258.604). FJB has participated in Advisory Boards for Merck, Eisai, and Agenus; and has received research funding from Eisai, Clovis, ImmunoGen, Merck, and Beigene (all outside the submitted work). TLW has no significant conflicts of interest related to this manuscript; financial disclosures that are not related: she has received research support to the institution for clinical trials from AbbVie, AstraZeneca, Clovis Oncology, Mersana, Mirati, Novartis, Roche Genentech, and Tesaro-GSK. LD has received personal fees from AstraZeneca, Genentech/Roche, MorphoTek, Merck, Inovio, Advance Medical, UpToDate, Cue Biopharma, British Journal of Obstetrics and Gynaecology, Parexel, State of California, Elsevier, ASCO, Expert review, ClearView Heath Care, National Cancer Institute, and JB Learning; and has received grants from Genentech/Roche, Cerulean/NextGen, AbbVie, Tesaro, Pfizer, GSK/Novartis, Morab, MorphoTek, Merck, Aduro BioTech, Syndax, Ludwig, LEAP Therapeutics, Eisai, Lycera, Inovio, and Advaxis; she reports other disclosures from Merck, GSK/Novartis and Genentech/Roche. IC has received travel grants from Tesaro; and is an advisor for AstraZeneca and GSK. PSO has no conflicts of interest related to this manuscript; financial disclosures that are not related to the current work: EMD Serono, Symphogen, Providence, and Tessa Therapeutics. GFF participates in an Advisory Board for GSK; has received honoraria from UpToDate; has received reviewer compensation from Journal of Clinical Oncology and Lancet Oncology; and has received payments to institution for clinical trial conduct from Roche, Syros, GSK, Iovance, Sermonix, Comugen, Cellex, Corcept, and Plexxikon. No disclosures were reported by the other authors., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Endometrial cancer (EC) is the most common gynecologic cancer in the U.S. The objective of this cohort study was to characterize the clinical and pathologic features that are associated with endometrial cancer-specific death for women cared for at a single National Cancer Institute-designated comprehensive cancer center., Patients, Materials, and Methods: This is a retrospective cohort from 2014 to 2017 including all women who had a hysterectomy for EC. Charts were reviewed for clinical and pathologic data, focusing on survival outcomes., Results: Seven hundred seventy-one patients with EC underwent hysterectomy with 760 informative for outcomes. Seventy-six (10%) deaths were related to their EC; 62 women died from recurrent EC. Nonendometrioid histology and advanced stage were predictors of recurrence and EC death. Among patients with endometrioid ECs, mismatch repair status was significantly associated with EC-specific survival (relative risk = 4.8; 95% confidence interval, 2.3-10.3; p < .0001). Most patients with EC who recurred died of their disease 62/83 (74.7%). Nearly half of the patients that recurred (27/62) had no additional therapy at the time of recurrence. Overall survival was significantly longer for those women who had additional treatment at the time of recurrence; however, the improvement in overall survival with therapy at recurrence was largely attributable to effects in those women who were adjuvant therapy naïve., Conclusion: Although there is benefit of treatment at the time of recurrence for treatment-naïve women; only approximately half of patients were able to receive therapy. There is an urgent need for continued efforts for more effective EC therapy in both the front-line and recurrent setting as well as early identification of cancer diagnosis and recurrence., Implications for Practice: Approximately 10% of patients died of their endometrial cancer. Most deaths were from recurrent disease; however, almost 20% of endometrial cancer deaths were within 120 days of surgery. Although treatment at the time of recurrence improves overall survival, only approximately half of patients will receive therapy at the time of recurrence. Traditional prognostic features like histology and stage remain important to predict risk of recurrence, and newer biomarkers, such as mismatch repair status, may improve risk stratification and targeted therapy. There remains an urgent need for improved therapy and early detection of diagnosis and recurrence., (© 2021 AlphaMed Press.)

Background: There is a paucity of literature regarding the outcomes following vulvar excision for nonmalignant lesions. This is a common procedure among gynecologists and gynecologic oncologists, and a body of evidence is warranted to guide clinical care and future research., Objective: This study aimed to estimate the rate of wound complications following simple vulvar excision and to identify the risk factors for these outcomes. Our secondary objectives were to determine the rates of (1) positive margins and (2) occult carcinoma in the cases of vulvar dysplasia., Study Design: We conducted a single-institution, retrospective cohort study of the patients who underwent simple vulvar excision procedures for suspected premalignant or benign lesions between June 2016 and February 2020. Our primary outcome was the rate of composite wound complications, including wound separation or breakdown, infection, or hematoma. Our secondary outcomes were the incidence of (1) margins positive for residual dysplasia and (2) occult minimally invasive carcinoma. The Fisher exact tests and chi-squared tests were used to compare the categorical variables and logistic regression models and independent student t tests were used for continuous variables, as appropriate. Multivariate stepwise selection and multiple logistic regression was performed to evaluate the risk factors for complications and generate the odds ratios., Results: Of the 338 patients included in the study, 143 (42.3%) experienced wound complication. Most of these complications were wound separation or breakdown (n=134, 39.6%), followed by infection (n=22, 6.5%), and hematoma (n=4, 1.2%). On multivariate analysis, the presence of high-grade vulvar dysplasia (adjusted odds ratio, 1.83; 95% confidence interval, 1.06-3.15), longer specimen diameter (adjusted odds ratio, 1.03; 95% confidence interval, 1.01-1.05), and lesion location on the perineum (adjusted odds ratio, 2.25; 95% confidence interval, 1.38-3.66) were independent risk factors. With high-grade vulvar dysplasia, the rate of positive margins was 50.2% (114/227) and that of occult microinvasive carcinoma was 17.2% (39/227). Notably, the primary and secondary outcomes were similar among gynecologic oncologists and gynecologists., Conclusion: Wound complications following vulvar excision for nonmalignant lesions are common. Select groups may benefit from anticipatory counseling and future interventional studies to prevent complication. The incidence of positive surgical margins and occult minimally invasive carcinoma is also high, reflecting the challenging nature of treating vulvar disease., (© 2021 The Authors.)

•Chemotherapy initiation and subsequent tumor lysis can release immunogenic antigens.•Advanced staged ovarian cancer associated with dermatomyositis.•PARP Inhibitor initiation can worsen paraneoplastic syndromes like dermatomyositis.•Signs and symptoms of dermatomyositis can be confused with chemotherapy side-effects., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Objectives: To estimate the maximally tolerated dose (MTD) and describe toxicities associated with lenvatinib and weekly paclitaxel in patients with recurrent endometrial and platinum resistant epithelial ovarian cancer., Methods: Using a 3 + 3 design patients were given weekly paclitaxel 80 mg/m2 IV day 1, 8, 15 and oral levantinib daily on a 28-day cycle. Lenvatinib dose levels were 8 mg, 12 mg, 16 mg, 20 mg. Toxicities were recorded using CTCAE v4.03 and response was determined with imaging after cycle 2, then every 3rd cycle, using RECIST 1.1 criteria., Results: 26 patients were enrolled; 19 with ovarian cancer (14 high grade serous, 1 low grade serous, 2 clear cell, 1 endometrioid, and 1 carcinosarcoma), and 7 with endometrial cancer (3 serous, and 4 endometrioid). The MTD was established at lenvatinib 16 mg and weekly paclitaxel 80 mg/m2. Toxicities (all grades) occurring in ≥25% of patients included anemia, neutropenia, lymphopenia, mucositis, nausea, diarrhea, anorexia, hypertension, fatigue, proteinuria, epistaxis, hoarseness. Twenty-three patients were evaluable for response and PFS; 15 (65%) had a partial response, 7 (30%) stable, 1 (4%) progressive disease with an objective response rate of 65%; 71% in ovarian and 50% in endometrial cancer. Median progression free survival (PFS) is 12.4 months; 14.0 months in endometrial cancer, 7.2 months in ovarian cancer; 54% had a PFS > 6 months. The median duration of response for PR patients (n = 15) was 10.9 months., Conclusions: The regimen was tolerable with manageable side effects. Encouraging activity was observed in endometrial and ovarian cancer, and warrants further development., Competing Interests: Declaration of Competing Interest Dr. Backes reports grants and personal fees from Eisai, grants and personal fees from Merck, grants from Immunogen, grants and personal fees from Clovis, personal fees from Agenus, AstraZeneca, Genentech, GlaxoSmithKline, all outside the submitted work. Dr. O'Malley reports personal fees from AstraZeneca, Tesaro/GSK, Immunogen, Ambry, Janssen/J&J, Abbvie, Regeneron, Amgen, Novocure, Genentech/Roche, GOG Foundation, Iovance Biotherapeutics, Inc., Myriad Genetics, Eisai, Agenus, Tarveda, Merck, SeaGen, Novartis, Mersana, Clovis, Rubis, Elevar, outside the submitted work. Dr. Salani reports personal fees from Glaxo Smith Kline, Clovis, Iovance, Seattle Genetics, Merck, Astra Zeneca, outside the submitted work. Dr. Hays reports personal fees from Clovis, AstraZeneca, Merck, Tesaro, Ipsen, Seattle Genetics, outside the submitted work. Dr. Copeland reports personal fees from Myriad Genetics, GlaxoSmithKline, Elevar, Toray Therapeutics, Rubius Therapeutics, Sorrento Therapeutics, outside the submitted work. None of the other authors (KB, CC, MP, KD, KH, MC, DC, MP, JF) have a significant conflict of interest related to the current study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose of Review: This article will discuss the recent data on the prognostic significance of molecular classification of endometrial carcinoma, as well as its impact on directing treatment decisions., Recent Findings: Molecular classification has emerged as a complement to the current paradigm of endometrial cancer (EC) risk stratification. POLE mutations appear to portend favorable prognoses, but data are insufficient to indicate withholding treatment based on this signature. Copy number high (CNH) EC carries a worse prognosis and may benefit from more aggressive therapy. MMRd tumors are likely to have other prognostic features that indicate adjuvant treatment and many recurrences respond favorably to pembrolizumab. Progression of molecular profiling may allow further discrimination of the no specific molecular profile (NSMP) group. Treatment for this group remains largely based on conventional risk factors. For both the NSMP and the CNH groups, treatment with lenvatinib and pembrolizumab is an attractive contemporary option for recurrence management. Molecular classification is a useful adjunct to conventional risk stratification paradigms for both prognostic counseling and treatment selection. Clinical trials incorporating molecular signatures in assigning treatment strategies may further elucidate the value of this classification system.

Objectives: To assess associations between treatment and recurrence-free survival (RFS) among patients with isolated tumor cells (ITCs) in sentinel lymph nodes (SLN) and otherwise stage I/II endometrioid endometrial cancer (EC)., Methods: A multi-institutional retrospective study of patients with SLN ITCs (<200 cells and < 0.2 mm) was performed. Only patients with otherwise stage I/II EC, endometrioid histology, and no evidence of micro-or macrometastases were included. Univariate and multivariable Cox proportional hazard models were used to evaluate associations between treatment, tumor characteristics, and RFS., Results: 175 patients were included. Median follow up time was 31 months. 39% stage IB and 12% stage II disease. 76 (43%) received no adjuvant therapy or vaginal brachytherapy only (NAT/VBT), 21 (12%) had external beam radiation (EBRT), and 78 (45%) received chemotherapy +/- radiation. Patients who received chemotherapy more often had tumors with deep myoinvasion, lymphovascular space invasion (LVSI), and higher grade. Nine (5.1%) patients recurred; 5 distant, 3 retroperitoneal, and 1 vaginal. Extra-vaginal recurrences were similar in patients with or without chemotherapy (5.2% vs 3.8%, p = 0.68). After controlling for stage, LVSI and grade, chemotherapy and EBRT were not associated with RFS (HR = 0.63, 95%CI 0.11-3.52, and HR = 0.90, 95%CI 0.22-3.61, respectively). Type of lymph node dissection and ITC detection method were not associated with RFS., Conclusions: Risk of retroperitoneal and/or distant recurrence is low (4.6%) for patients with stage I/II endometrioid EC and ITCs in SLNs regardless of treatment. Our preliminary data suggests that adjuvant therapy may not be significantly associated with RFS. However, longer follow-up time and a larger sample size are needed before definitive recommendations regarding adjuvant therapy for patients with EC and only ITCs in SLN can be made., Competing Interests: Declaration of Competing Interest Dr. Leitao reports personal fees from JnJ/Ethicon, outside the submitted work; and Dr. Leitao is an ad hoc speaker for Intuitive Surgical, Inc. Dr. Abu-Rustum reports grants from GRAIL, grants from Stryker, outside the submitted work. Dr. Backes reports grants and personal fees from Eisai, grants and personal fees from Merck, grants from Immunogen, grants and personal fees from Clovis, personal fees from Agenus, personal fees from AstraZeneca, personal fees from Genentech, personal fees from GlaxoSmithKline, all outside the submitted work. None of the other authors have a significant conflict of interest related to the current study. Some of the investigators (Felix, Abu-Rustum, Leitao) receive grants for other projects that fund part of their time., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women. This manuscript, Part II in a two-part series, includes specific recommendations on treatment of recurrent disease, post treatment surveillance and survivorship, considerations for younger women, and special situations. Part I covered histopathology and molecular pathology, risk factors, presentation and diagnostic approach, surgical approach and adjuvant therapy., Competing Interests: Declaration of Competing Interest The authors of this paper report that they have no conflicts of interest related to any of the content of this manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Pten fl/fl . In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance and loss of efficacy. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease. These results suggest that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC that are dependent on disease stage. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquired Trp53 mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response., (Copyright © 2020. Published by Elsevier Inc.)

Objective: A pathologic chemotherapy response score (CRS) is used to grade ovarian cancer response to neoadjuvant chemotherapy (NACT). We evaluated the prognostic significance of the CRS in a single institution cohort., Methods: A retrospective review of all consecutive epithelial ovarian cancer patients undergoing interval debulking surgery (IDS) after NACT from 2016 to 2017 were included. Clinical, pathologic, surgical, outcomes, and genetic data were abstracted from medical records. CRS was assigned by pathology based on a section of omentum as follows: 1 = minimal response, 2 = moderate response, and 3 = near complete response., Results: Among the 50 subjects, 14 (28%) were classified as CRS1, 29 (58%) as CRS2, and 7 (14%) as CRS3. The majority of patients were diagnosed with high grade serous histology (94%). Most women in this cohort underwent either an optimal or complete cytoreduction to no gross residual disease (96%). Women in the CRS2 group were most likely to have a pathogenic variant (51.7%) while those in the CRS1 were least likely (7.1%). Most women recurred regardless of CRS. CRS was not associated with progression-free survival (log-rank p = 0.82) or overall survival (log-rank p = 0.30)., Conclusions: Though previous data support the use of CRS as a prognostic indicator, we failed to show a correlation between CRS and survival in our continuous single institution cohort. The high rate of optimal debulking across all CRS groups in this study may mitigate the prognostic significance of the scoring system. Nevertheless, tumors that respond poorly to traditional chemotherapy should remain of avid interest for potential novel therapies., (Published by Elsevier Ltd.)

Purpose: Uterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002., Patients and Methods: Eligible patients had stage III to IV or recurrent disease. Participants were randomized 1:1 to receive C/P for six cycles ± T followed by maintenance T until progression or toxicity. Progression-free survival (PFS) was the primary endpoint; overall survival (OS) and toxicity were secondary endpoints., Results: Sixty-one patients were randomized. After a median-follow-up of 25.9 months, 43 progressions and 38 deaths occurred among 58 evaluable patients. Updated median-PFS continued to favor the T-arm, with medians of 8.0 months versus 12.9 months in the control and T-arms (HR = 0.46; 90% CI, 0.28-0.76; P = 0.005). Median-PFS was 9.3 months versus 17.7 months among 41 patients with stage III to IV disease undergoing primary treatment (HR = 0.44; 90% CI, 0.23-0.83; P = 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR = 0.12; 90% CI, 0.03-0.48; P = 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR = 0.58; 90% CI, 0.34-0.99; P = 0.046). The benefit was most notable in those with stage III to IV disease, with survival median not reached in the T-arm versus 24.4 months in the control arm (HR = 0.49; 90% CI, 0.25-0.97; P = 0.041). Toxicity was not different between arms., Conclusions: Addition of T to C/P increased PFS and OS in women with advanced/recurrent HER2/Neu-positive USC, with the greatest benefit seen for the treatment of stage III to IV disease., (©2020 American Association for Cancer Research.)

Background: Endometrial intraepithelial neoplasia, also known as complex atypical hyperplasia, is a precancerous lesion of the endometrium associated with a 40% risk of concurrent endometrial cancer at the time of hysterectomy. Although a majority of endometrial cancers diagnosed at the time of hysterectomy for endometrial intraepithelial neoplasia are low risk and low stage, approximately 10% of patients ultimately diagnosed with endometrial cancers will have high-risk disease that would warrant lymph node assessment to guide adjuvant therapy decisions. Given these risks, some physicians choose to refer patients to a gynecologic oncologist for definitive management. Currently, few data exist regarding preoperative factors that can predict the presence of concurrent endometrial cancer in patients with endometrial intraepithelial neoplasia. Identification of these factors may assist in the preoperative triaging of patients to general gynecology or gynecologic oncology., Objective: To determine whether preoperative factors can predict the presence of concurrent endometrial cancer at the time of hysterectomy in patients with endometrial intraepithelial neoplasia; and to describe the ability of preoperative characteristics to predict which patients may be at a higher risk for lymph node involvement requiring lymph node assessment at the time of hysterectomy., Materials and Methods: We conducted a retrospective cohort study of women undergoing hysterectomy for pathologically confirmed endometrial intraepithelial neoplasia from January 2004 to December 2015. Patient demographics, imaging, pathology, and outcomes were recorded. The "Mayo criteria" were used to determine patients requiring lymphadenectomy. Unadjusted associations between covariates and progression to endometrial cancer were estimated by 2-sample t-tests for continuous covariates and by logistic regression for categorical covariates. A multivariable model for endometrial cancer at the time of hysterectomy was developed using logistic regression with 5-fold cross-validation., Results: Of the 1055 charts reviewed, 169 patients were eligible and included. Of these patients, 87 (51.5%) had a final diagnosis of endometrial intraepithelial neoplasia/other benign disease, whereas 82 (48.5%) were ultimately diagnosed with endometrial cancer. No medical comorbidities were found to be strongly associated with concurrent endometrial cancer. Patients with endometrial cancer had a thicker average endometrial stripe compared to the patients with no endometrial cancer at the time of hysterectomy (15.7 mm; standard deviation, 9.5) versus 12.5 mm; standard deviation, 6.4; P = .01). An endometrial stripe of ≥2 cm was associated with 4.0 times the odds of concurrent endometrial cancer (95% confidence interval, 1.5-10.0), controlling for age. In all, 87% of endometrial cancer cases were stage T1a (Nx or N0). Approximately 44% of patients diagnosed with endometrial cancer and an endometrial stripe of ≥2 cm met the "Mayo criteria" for indicated lymphadenectomy compared to 22% of endometrial cancer patients with an endometrial stripe of <2 cm., Conclusion: Endometrial stripe thickness and age were the strongest predictors of concurrent endometrial cancer at time of hysterectomy for endometrial intraepithelial neoplasia. Referral to a gynecologic oncologist may be especially warranted in endometrial intraepithelial neoplasia patients with an endometrial stripe of ≥2 cm given the increased rate of concurrent cancer and potential need for lymph node assessment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved to treat recurrent ovarian cancer with BRCA1 or BRCA2 mutations, and as maintenance therapy for recurrent platinum-sensitive ovarian cancer (BRCA wild-type or mutated) after treatment with platinum. However, the acquired resistance against PARPi remains a clinical hurdle. Here, we demonstrated that PARP inhibitor (olaparib)-resistant epithelial ovarian cancer (EOC) cells exhibited an elevated aldehyde dehydrogenase (ALDH) activity, mainly contributed by increased expression of ALDH1A1 due to olaparib-induced expression of BRD4, a member of bromodomain and extraterminal (BET) family protein. We also revealed that ALDH1A1 enhanced microhomology-mediated end joining (MMEJ) activity in EOC cells with inactivated BRCA2, a key protein that promotes homologous recombination (HR) by using an intrachromosomal MMEJ reporter. Moreover, NCT-501, an ALDH1A1-selective inhibitor, can synergize with olaparib in killing EOC cells carrying BRCA2 mutation in both in vitro cell culture and the in vivo xenograft animal model. Given that MMEJ activity has been reported to be responsible for PARPi resistance in HR-deficient cells, we conclude that ALDH1A1 contributes to the resistance to PARP inhibitors via enhancing MMEJ in BRCA2 -/- ovarian cancer cells. Our findings provide a novel mechanism underlying PARPi resistance in BRCA2-mutated EOC cells and suggest that inhibition of ALDH1A1 could be exploited for preventing and overcoming PARPi resistance in EOC patients carrying BRCA2 mutation., (©2019 American Association for Cancer Research.)

Introduction: Optimization of preoperative nutritional status has been recommended and associated with improved outcomes for other oncologic procedures, but has not been studied in patients undergoing pelvic exenteration., Methods: A retrospective chart review of 199 patients was conducted. Overall survival (OS) was calculated using the Kaplan-Meier method and multivariate analysis was performed with Cox proportional hazards., Results: 199 patients underwent PE with 61 (31%), 78 (40%) and 58 (29%) patients having colorectal, gynecologic and urologic histological diagnoses, respectively. Median OS following PE was 25 months. Preoperative serum albumin <3.5 g/dL was associated with worsened OS (HR 1.661; 95% CI 1.052-2.624) as well as increased incidence of any postoperative complication (85.9% vs 72.3%, p = 0.034), but was not associated with 90-day mortality (11.3% vs 7.9%, p = 0.457)., Conclusion: Poor preoperative nutritional status is associated with increased complications and decreased OS. Surgeons should maximize preoperative nutritional status to improve perioperative outcomes and long-term survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)